One of the most exciting advances in biomedical research is the introduction of genome biology, which enables the researcher to gain a global view at high resolution. The invention of next generation (NextGen) sequencers greatly accelerates the integration of genome technology into other research fields and essentially brings the genome center capacity to individual research laboratories. NextGen sequencing has revolutionized the world of molecular biology, genetics, and genomics. The requested instrument will transform the way scientists from a broad range of disciplines conduct research to understand the molecular mechanisms of human diseases, including disease gene cloning, cancer, gene expression, splicing, development and differentiation, and epigenetics. We will apply the system to several different technologies, including: 1) identifying direct downstream targets of transcription factors by ChIP-Seq;2) performing transcriptome analysis of human tissues and model organisms by RNA-Seq;3) identifying and cloning human disease genes by whole genome and targeted capture deep sequencing;4) investigating alternative splicing and human diseases by splicing junction sequencing;and 5) examining affects of environment and nutrition on pregnancy, development, and disease by examining the epigenome through whole genome bisulfate sequencing and histone modifications. As the participating PIs all engage in both basic and clinical research including three who hold an M.D. degree, we believe the introduction of the single molecule sequencing (SMS) technology will have direct, strong, and immediate impact on many medically relevant fields.